Damage to the stomach lining, such as from acid reflux or helicobacter pylori (H. pylori) infections, might reactivate the newly found signaling pathway – but in this situation it would work in the opposite direction. As a result, the lining reverts to a more generic intestinal type of cells that form cancer-prone lesions.
Ramesh Shivdasani, MD, PhD, of Dana-Farber, senior author of a report in the April 4 issue of Developmental Cell, said the finding "opens a window that could help us eventually interfere with these pathways when they become abnormal. It should give us a list of potential therapeutic targets and could even help us to prevent the development of the precancerous lesions."
The lead author is Byeong-Moo Kim, PhD, also of Dana-Farber.
Patients with the increasingly common disorder known as Gastroesophageal Reflux Disease, or GERD, are at risk of developing precancerous lesions in the upper end of the stomach or the adjoining lower end of the esophagus. These lesions require intense frequent monitoring by endoscopy and sometimes prophylactic surgery to decrease the threat of this dangerous form of cancer. Cancer of the "gastroesophageal junction" has increased dramatically in the past two decades, especially in patients younger than 40 years.
Shivdasani's laboratory studies the "rules" according to which body tissues develop their distinctive form and function at the beginning of life, because they may be reactivated, abnormally, when cancer arises later.
"Cancers of the stomach are almost always preceded by the conversion of the stomach type of lining to an intestinal type," says Shivdasani. In the developing fetus, the entire digestive tract is initially lined with intestinal-type cells. At a certain point, the activation of a molecular signaling pathway causes this layer to become more specialized, or differentiated, for the lining of the stomach and esophagus. Thereafter, the pathway falls silent, unless, many years later, damage to the lining sets it in motion again.
In the mouse fetus, the differentiation of intestinal lining into stomach lining happens rapidly, during a window of only one day, around the 12th and 13th days of gestation. (The corresponding period in the human fetus is during the 8th to 10th weeks.)
"We found that the epithelium [lining layer] is malleable, and depends completely on this pathway to instruct it to become stomach," says Shivdasani. "In the absence of this pathway, the epithelium would develop into the default intestinal state."
In experiments in mice, and with cultured mouse stomach and intestinal tissue, the scientists demonstrated that the signals that drive the differentiation of stomach lining are sent by a layer of cells, known as mesenchyme, that lie directly beneath the intestinal lining. The key player in the signaling pathway, they found, is a transcription factor – a protein that governs the expression of genes under its control – called Barx1. The main action of Barx1 in stomach lining formation is to block signaling through another pathway known as Wnt, the scientists found.
"Barx1 gives us a handle on what elements of the pathway might allow the stomach to differentiate abnormally into intestine as a result of injury to the stomach lining, setting the stage for cancer," Shivdasani says.
"These research findings offer the hope of identifying a protein marker that can be used to screen for these diseases and even to serve as a target for newly designed forms of therapy," said Robert Mayer, MD, director of Dana-Farber's Center for Gastrointestinal Oncology, who was not involved in the study.
Other authors of the report were at the Institute for Craniofacial Biology at Kings College in London, who supplied genetically engineered mice used in the experiments.
The work was supported by the Robert Black Charitable Foundation, the National Institutes of Health, and the Wellcome Trust and UK Medical Research Council.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.
Journal
Developmental Cell